Introduction

Hematopoietic cell transplantation (HCT) can possibly cure a variety of
genetic disorders, including sickle cell disease1. The goal
of this treatment is to eliminate the sickle erythrocyte and its cellular
progenitors and replace them with donor hematopoietic pluripotent stem
cells that produce erythrocytes expressing at best no sickle hemoglobin
or at worse quantities similar to the trait condition. The risk of severe
adverse events after transplantation is weighed against the possibility
of preventing serious complications from sickle cell disease. These complications
can produce extensive morbidity and in some cases, early death. The first
reports of a successful transplantation (level IV evidence) have been confirmed
and extended by several multicenter level III investigations (Table 1).
To date, nearly all the transplants performed have utilized HLA-identical
sibling donors, which limits the number of sickle cell patients eligible
for this therapy. No level II or I studies exist to support this therapeutic
option for sickle cell disease. However, as new therapies are developed
that prevent and treat graft-versus-host and host-versus-graft reactions
(which are the primary contributors to the histocompatibility barriers),
transplantation likely will take on added importance for selected patients
with sickle cell disease.

Indications for HCT

Table 1. Supporting Evidence for HCT in Sickle Cell Disease

Study Description

First Author

Strength of Evidence

Case report

Johnson2, Milpied3

IV

Patient series

Vermylen7,27

IV

HCT trial proposed

Thomas28

V

Collaborative HCT trial

Walters8

III

European collaborative trial

Vermylen29

III

Long-term impact of HCT

Vermylen9, Walters12

III

UCB report

Brichard20, Minero30

IV

The first published reports of HCT for sickle cell disease involved
patients who had other more deadly hematological or genetic disorders that
were the primary indication for transplantation2,3 (Table 1).
This initial experience showed elimination of sickle cell disease with
engraftment of donor hematopoietic stem cells. In the following decade
or more, considerable discussion centered on who should be considered and
when they should be referred for transplantation4-6. The first
limited series of patients who underwent transplantation as specific therapy
for sickle cell disease comprised a group of families from Africa living
at the time in Belgium7. Based in part on the very good outcome
experienced by these initial patients, several multicenter phase II studies
for children with symptomatic sickle cell disease were conducted in North
America and Europe8,9. Children were felt to be better candidates
for bone marrow transplantation than adult patients because of their lower
risk of transplant-related complications such as graft-versus-host disease
(GVHD), and because of a presumed lower burden of sickle-related organ
damage. Table 2 summarizes the inclusion and exclusion criteria for enrollment
adopted by one multicenter study.

Current results of HCT from HLA-identical sibling donors

Approximately 150 patients have undergone HCT from HLA-identical siblings
worldwide9-12. The combined results of 3 level III studies have
demonstrated that more than 90% of patients survive and approximately 85%
survive free from sickle cell disease after transplantation with a period
of followup that extends to 11 years. Sickle cell disease recurred in approximately
10% of patients after transplantation. Neurologic complications such as
seizures occurred frequently after transplantation, requiring development
of preventative measures13-15. Among patients who had stable
engraftment of donor cells, no subsequent sickle cell-related clinical
events occurred and their pre-existing sickle cell-related organ damage
stabilized9,12,16. Splenic function also recovered17.
Some patients developed mixed donor-host hematopoietic chimerism after
transplantation that was stable18. Interestingly, these patients
also had no symptoms from sickle cell disease. Primary and secondary amenorrhea
were common among females after transplantation and most patients likely
will be infertile9,12. The risk of secondary cancers after HCT
remains uncertain but it is estimated to be less than 5 percent19.
Linear growth was normal or accelerated after transplantation in most patients9,12.

Table 2. Eligibility Criteria for HCT for Sickle Cell Disease

Inclusions

Patients < 16 years of age with sickle cell anemia (SS or Sb0-thalassemia)

One or more of the following complications:

Stroke or CNS event lasting longer than 24 hours

Recurrent acute chest syndrome

Recurrent vaso-occlusive painful episodes

Impaired neuropsychologic function and abnormal cerebral MRI scan

Stage I-II sickle lung disease

Sickle nephropathy (GFR 30-50 percent of predicted normal)

Osteonecrosis of multiple joints

Exclusions

Patients > 16 years of age

HLA-non-identical donor

One or more of the following conditions:

Lansky performance score <70 percent

Acute hepatitis or biopsy evidence of cirrhosis

Renal impairment (GFR <30 percent predicted normal)

Stage III-IV sickle lung disease

Transplantation from alternative sources of stem cells

Umbilical cord blood (UCB) and hematopoietic cells from volunteer donors
are alternative sources of hematopoietic stem cells that could increase
the number of donors for sickle cell disease patients. UCB transplantation
for sickle cell disease has been successful20. No published
report exists of transplantation from volunteer unrelated donors. UCB possibly
produces less GYHD than does standard bone marrow transplantation (level
III evidence)21. A downside to UCB transplantation is slower
hematopoietic engraftment and perhaps a higher rate of graft rejection22.
The relatively low number of hematopoietic stem cells recovered from UCB
effectively limits the procedure to children. Strategies for transplantation
from unrelated volunteer stem cell donors must surmount the histocompatibility
barriers associated with higher rates of GVHD and graft rejection to become
viable options. Currently, no protocol for transplantation from alternative
sources of stem cells exists, although pilot clinical investigations are
being explored.

HCT for adults with sickle cell disease

Very little information exists concerning the outcome after HCT among adults.
The risk of death with the procedure may be higher, due in part to the
higher frequency of GVHD23. The risk of death clearly is greater
after HCA-identical bone marrow transplantation in adults with sickle cell
disease relative to transplants in younger patients with b
-thalassemia24. Non-myeloablative preparation before HCT could
clinically correct sickle cell disease with lower risk of severe complications25.
The aim is to establish stable donor-host hematopoietic chimerism after
transplantation, which might provide a significant clinical benefit to
patients. If successful, this approach might improve the safety profile
of HCT for older people with advanced organ damage from sickle cell disease.
Several ongoing investigations seek to test this hypothesis.

Summary of the State of the Art

Currently, HCT is the only therapy that can cure sickle cell disease. The
results of transplantation are best when performed in children with a sibling
donor who is HLA-identical. While there appears to be a considerable benefit
to those who survive with stable engraftment of donor cells, there are
also significant health risks to those who undergo this treatment. Therefore,
careful discussions with families by health care professionals experienced
in the care of patients with sickle cell disease and with HCT should be
conducted to ensure informed consent for this procedure. Presently, HCT
is reserved for patients who have experienced significant complications
of sickle cell disease, such as stroke, recurrent episodes of acute chest
syndrome or intractable vaso-occlusive pain. With better understanding
of the complex pathophysiology of sickle cell disease, we may one day have
clinical or genetic markers that reliably predict a severe clinical course.
We could then apply HCT before significant complications occur. Current
research efforts are aimed at expanding donor availability by overcoming
graft-versus-host and host-versus-graft reactions. Non-myeloablative preparation
for the purpose of establishing stable donor-host hematopoietic chimerism
could further reduce the toxicity of HCT. These efforts in aggregate should
expand the role of HCT in treating patients with sickle cell disease.

Recommendations

Children with sickle cell disease who experience significant, non-infectious
complications caused by vaso-occlusion should be considered for HCT. If
full-siblings are available, HLA typing should be performed (refer to Table
2). Families should receive counseling about the collection of UCB from
future pregnancies26. For severely affected children who have
HLA-identical sibling donors, families should be informed of the risks,
benefits and alternatives to interventions such as HCT. These carefully
selected patients should be offered the treatment option of HCT. No level
II study exists to recommend HCT over an alternate intervention such as
chronic blood transfusion.

Treatment Protocol

The treatment plan outlined below is that followed by one of the multicenter
investigations of HCT for sickle cell disease8:

Treatment

Day ó9 to -6

Day -5

Day -4

Day -3

Day -2

Day -1

Day 0

posttransplant

Busulfan

X

X

-

Cyclophosphamide

X

X

X

X

-

Anti-thymocyte
globulin

X

X

X

-

Marrow infusion

X

-

CSP

X

X

Through day +90

Methotrexate

Single doses on days +1, 3, 6,
11

Doses:
*Busulfan 3.5 mg/kg/day orally for a total dose of 14 mg/kg

Cyclophosphamide 50 mg/kg/day intravenously for a total dose of 200
mg/k